Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids
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Background and Aims: Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation. Approach and Results: The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA. Conclusions: Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.
| Original language | English |
|---|---|
| Journal | Hepatology |
| Volume | 76 |
| Issue number | 6 |
| Pages (from-to) | 1617-1633 |
| ISSN | 0270-9139 |
| DOIs | |
| Publication status | Published - 2022 |
Bibliographical note
Funding: information
This work was supported by “Ayudas para apoyar grupos de investigación del sistema Universitario Vasco” (IT971-16 to PA), MCIU/AEI/FEDER, UE (2018-095134-B-100 to PA and by the University of Basque Country COLAB20/01 to PA; Spanish Carlos III Health Institute (ISCIII) (FIS PI15/01132, PI18/01075, PI21/00922, and Miguel Servet Program CON14/00129 and CPII19/00008 to JMB; FIS PI14/00399, PI17/00022 and PI20/00186 to MJP; Sara Borrell [CD19/00254 to PMR]) cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); CIBERehd (ISCIII) to JMB, MJP, PMR, PA and LB); “Diputación Foral Gipuzkoa” (DFG15/010, DFG16/004 to JMB and 2020-CIEN-000067-01 to PMR), Department of Health of the Basque Country (2019111024 to MJP, 2017111010 to JMB, and 2020111077 to JMB and PA), “Euskadi RIS3” (2016222001, 2017222014, 2018222029, 2019222054, 2020333010 to JMB), BIOEF (Basque Foundation for Innovation and Health Research: EiTB Maratoia BIO15/CA/016/BD to JMB) and Department of Industry of the Basque Country (Elkartek: KK-2020/00008 to JMB); La Caixa Scientific Foundation (HR17-00601 to JMB). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to JMB). AMMF-The Cholangiocarcinoma Charity (EU/2019/AMMFt/001, to JMB and PMR). MRDG was funded by “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC de Bizkaia), MJP was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Program RYC-2015-17755), IL, AL and FG-R by the Basque Government (PRE_2016_1_0152, PRE_2018_2_0195 and PRE 2020 2 02500, respectively), AN-Z and BG-S by the UPV/EHU, AB-V by “Programa de especialización de Personal Investigador Doctor” at the UPV/EHU (2019-2020) and MA by the MCIU/AEI/FEDER. The funding sources were not involved in the study design, data collection and analysis, decision to publish, or preparation of the article.
ID: 299198244